Sildenafil Administration to Treat Neonatal Encephalopathy

NCT02812433 | Completed Phase 1 DMC

• 1 other identifier: SANE-01
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

Despite improvements in neonatal care, birth asphyxia in term newborns remains a serious condition causing significant mortality and long-term morbidity, including cerebral palsy and mental retardation. Currently, no treatment exists to repair brain injuries secondary to neonatal asphyxia. The only available treatment for this condition is hypothermia that may prevent but not repair the development of brain injury. The success of this therapy is limited. Sildenafil already is used with some newborns for other purposes (i.e., persistent pulmonary hypertension), but, surprisingly, its effect on the newborn brain has never been studied systematically. The findings of the investigators in the rat model of term neonatal encephalopathy demonstrated that the administration of sildenafil following asphyxia promotes brain injury recovery. Thus, the investigators hypothesize that sildenafil may improve neurodevelopmental outcome in term asphyxiated newborns, in whom hypothermia treatment has failed to prevent the development of brain injury.

Conditions

Neonatal Encephalopathy

Keywords

birth asphyxia; brain; hypoxic-ischemic encephalopathy; neonate; neuroprotection; neurorestoration; newborn; sildenafil

Outcome Measures

Primary Outcomes (1)

• Serious adverse events

  Close monitoring for adverse events such as death, hypotension, persistent pulmonary hypertension, altered renal or hepatic function, etc to assess the safety of sildenafil

  Day 1 to 14 of life

Secondary Outcomes (1)

• Plasmatic concentrations of sildenafil and N-desmethyl sildenafil

  Day 2 to 10 of life

Other Outcomes (3)

• Brain injury severity as per a previously described brain injury score

  Day 30 of life, compared to day 2 of life

• panel of 45 inflammatory biomarkers known to be involved in neuroinflammation, including interleukin-1 (IL-1) alpha and its receptor, interleukin-6 (IL-6) and tumor necrosis factor (TNF) alpha

  Day 2 to 30 of life

• Bayley Scale of Infant Development (BSID-III)

  1 year and 2 years of age

Study Arms (2)

Sildenafil

ACTIVE COMPARATOR

Sildenafil 2 mg/kg/dose per os twice a day for seven consecutive days (from day 2 of life to day 9 of life) if brain injury on day 2 of life

Drug: Sildenafil

Ora-Blend

PLACEBO COMPARATOR

Ora-Blend 2 mg/kg/dose per os twice a day for seven consecutive days (from day 2 of life to day 9 of life) if brain injury on day 2 of life

Drug: Ora-Blend

Interventions

Sildenafil DRUG

sildenafil 2 mg/kg/dose per os twice a day for seven consecutive days (from day 2 of life to day 9 of life) if brain injury on day 2 of life

Sildenafil

Ora-Blend DRUG

Ora-Blend, 2 mg/kg/dose per os twice a day for seven consecutive days (from day 2 of life to day 9 of life) if brain injury on day 2 of life

Ora-Blend

Eligibility Criteria

• Age: 0 Minutes - 48 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and female asphyxiated newborns meeting the criteria for induced hypothermia:
• Gestational age ≥ 36 weeks and birth weight ≥ 1800 g
• Evidence of fetal distress, such as a history of an acute perinatal event, a cord pH ≤ 7.0 or base deficit ≤ - 16 mEq/L
• Evidence of neonatal distress, such as an Apgar score ≤ 5 at 10 minutes, a postnatal blood gas pH obtained within the first hour of life ≤ 7.0 or base deficit ≤ - 16 mEq/L, or a continued need for ventilation initiated at birth and continued for at least 10 minutes
• Evidence of moderate to severe neonatal encephalopathy by an abnormal neurological exam and/or an amplitude-integrated electroencephalogram (aEEG) These newborns will receive whole-body cooling to an esophageal temperature of 33.5°C, initiated within the first 6 hours of life, continued for 72 hours, and then they were slowly rewarmed using standard protocol .
• Evidence on a brain MRI performed on day 2 of life (while they are treated with hypothermia) of any type of brain parenchymal injury patterns typically encountered in asphyxiated newborns.
• If they meet the criteria for hypothermia treatment and demonstrate brain injury on day 2 of life, they will be randomized to sildenafil or placebo treatment.

You may not qualify if:

• Newborns with complex congenital heart disease
• Newborns with cerebral malformations
• Newborns with genetic syndrome
• Newborns with intraventricular and/or intraparenchymal hemorrhage on the MRI performed on day 2 of life
• Moribund infants not expected to survive

Sponsors & Collaborators

• McGill University Health Centre/Research Institute of the McGill University Health Centre: lead

Study Sites (1)

Montreal Children's Hospital

Montreal, Quebec, H3C1H3, Canada

Location

Related Publications (1)

• Wintermark P, Lapointe A, Steinhorn R, Rampakakis E, Burhenne J, Meid AD, Bajraktari-Sylejmani G, Khairy M, Altit G, Adamo MT, Poccia A, Gilbert G, Saint-Martin C, Toffoli D, Vachon J, Hailu E, Colin P, Haefeli WE. Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial. J Pediatr. 2024 Mar;266:113879. doi: 10.1016/j.jpeds.2023.113879. Epub 2023 Dec 22.

  PMID: 38142044 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Asphyxia Neonatorum; Hypoxia-Ischemia, Brain

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Pia Wintermark, Pia

  McGill University Health Centre/Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Paediatrics

Study Record Dates

• First Submitted: June 19, 2016
• First Posted: June 24, 2016
• Study Start: July 1, 2016
• Primary Completion: January 1, 2019
• Study Completion: January 1, 2022
• Last Updated: February 8, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)